Intramolecular C2 Domain-Mediated Autoinhibition of Protein Kinase C βII
The signaling output of protein kinase C (PKC) is exquisitely controlled, with its disruption resulting in pathophysiologies. Identifying the structural basis for autoinhibition is central to developing effective therapies for cancer, where PKC activity needs to be enhanced, or neurodegenerative dis...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2015-08-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124715007998 |
| _version_ | 1819231677341237248 |
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| author | Corina E. Antal Julia A. Callender Alexandr P. Kornev Susan S. Taylor Alexandra C. Newton |
| author_facet | Corina E. Antal Julia A. Callender Alexandr P. Kornev Susan S. Taylor Alexandra C. Newton |
| author_sort | Corina E. Antal |
| collection | DOAJ |
| description | The signaling output of protein kinase C (PKC) is exquisitely controlled, with its disruption resulting in pathophysiologies. Identifying the structural basis for autoinhibition is central to developing effective therapies for cancer, where PKC activity needs to be enhanced, or neurodegenerative diseases, where PKC activity should be inhibited. Here, we reinterpret a previously reported crystal structure of PKCβII and use docking and functional analysis to propose an alternative structure that is consistent with previous literature on PKC regulation. Mutagenesis of predicted contact residues establishes that the Ca2+-sensing C2 domain interacts intramolecularly with the kinase domain and the carboxyl-terminal tail, locking PKC in an inactive conformation. Ca2+-dependent bridging of the C2 domain to membranes provides the first step in activating PKC via conformational selection. Although the placement of the C1 domains remains to be determined, elucidation of the structural basis for autoinhibition of PKCβII unveils a unique direction for therapeutically targeting PKC. |
| first_indexed | 2024-12-23T11:48:46Z |
| format | Article |
| id | doaj.art-c650f394c8d446f09707acf389c72e84 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-23T11:48:46Z |
| publishDate | 2015-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-c650f394c8d446f09707acf389c72e842022-12-21T17:48:17ZengElsevierCell Reports2211-12472015-08-011281252126010.1016/j.celrep.2015.07.039Intramolecular C2 Domain-Mediated Autoinhibition of Protein Kinase C βIICorina E. Antal0Julia A. Callender1Alexandr P. Kornev2Susan S. Taylor3Alexandra C. Newton4Department of Pharmacology, University of California at San Diego, La Jolla, CA 92037, USADepartment of Pharmacology, University of California at San Diego, La Jolla, CA 92037, USADepartment of Pharmacology, University of California at San Diego, La Jolla, CA 92037, USADepartment of Pharmacology, University of California at San Diego, La Jolla, CA 92037, USADepartment of Pharmacology, University of California at San Diego, La Jolla, CA 92037, USAThe signaling output of protein kinase C (PKC) is exquisitely controlled, with its disruption resulting in pathophysiologies. Identifying the structural basis for autoinhibition is central to developing effective therapies for cancer, where PKC activity needs to be enhanced, or neurodegenerative diseases, where PKC activity should be inhibited. Here, we reinterpret a previously reported crystal structure of PKCβII and use docking and functional analysis to propose an alternative structure that is consistent with previous literature on PKC regulation. Mutagenesis of predicted contact residues establishes that the Ca2+-sensing C2 domain interacts intramolecularly with the kinase domain and the carboxyl-terminal tail, locking PKC in an inactive conformation. Ca2+-dependent bridging of the C2 domain to membranes provides the first step in activating PKC via conformational selection. Although the placement of the C1 domains remains to be determined, elucidation of the structural basis for autoinhibition of PKCβII unveils a unique direction for therapeutically targeting PKC.http://www.sciencedirect.com/science/article/pii/S2211124715007998 |
| spellingShingle | Corina E. Antal Julia A. Callender Alexandr P. Kornev Susan S. Taylor Alexandra C. Newton Intramolecular C2 Domain-Mediated Autoinhibition of Protein Kinase C βII Cell Reports |
| title | Intramolecular C2 Domain-Mediated Autoinhibition of Protein Kinase C βII |
| title_full | Intramolecular C2 Domain-Mediated Autoinhibition of Protein Kinase C βII |
| title_fullStr | Intramolecular C2 Domain-Mediated Autoinhibition of Protein Kinase C βII |
| title_full_unstemmed | Intramolecular C2 Domain-Mediated Autoinhibition of Protein Kinase C βII |
| title_short | Intramolecular C2 Domain-Mediated Autoinhibition of Protein Kinase C βII |
| title_sort | intramolecular c2 domain mediated autoinhibition of protein kinase c βii |
| url | http://www.sciencedirect.com/science/article/pii/S2211124715007998 |
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